USP25 Promotes Glycolysis of Acute Myeloid Leukemia Cells and Enhances Tumor Immunity

Acute myeloid leukemia (AML) is an incursionary hematopoietic tumor with frequent relapses and an unfavorable prognosis. Ubiquitin-specific peptidase 25 (USP25) mediates the progression of various cancers, but its role in AML remains uncharted. The expression of USP25 in AML was analyzed in silico, in vitro, and in vivo through real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. The function of USP25 in proliferation, apoptosis, glycolysis, and immunity in AML was addressed through cell counting kit-8 (CCK-8), flow cytometry, detection of glucose consumption, lactate production, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR), immunohistochemistry, immunofluorescence, and Western blot. The mechanism of USP25 in AML was explored via co-immunoprecipitation (Co-IP), ubiquitination, cycloheximide, and Western blot. Upregulation of USP25 indicated a poor overall survival in AML patients. Knock-in and knock-down results revealed that USP25 enhanced viability, the level of glucose consumption, lactate production, ECAR, and the level of anti-glucose transporter type 1 (GLUT1) and hexokinase-2 (HK2), but reduced the apoptosis rate and the OCR level. Mechanically, USP25 directly bound and deubiquitinated c-Myc. An upregulation of c-Myc and programmed cell death ligand 1 (PD-L1) was found in AML. Knockdown of c-Myc decreased USP25-induced cell viability, glucose consumption, and lactate production level. In vivo, knockdown of USP25 decreased tumor volume and weight, the ki-67 expression, and the levels of c-Myc and PD-L1, but elevated the levels of cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8). USP25 facilitated proliferation, glycolysis, and immunity through deubiquitinating c-Myc in AML. The results identified USP25 as a possible target for AML treatment.